The use of bifunctional chelating agents, such as EDTA, is well known in fields such as medicinal chemistry. They are used, for example, in the diagnosis and treatment of cancer. See, e.g., Sgouros, Encyclopedia of Cancer, Second Edition, (Vol. 4, New York, 2002, pp. 29-40).
To elaborate on the use of these chelators in, e.g., cancer diagnosis and therapy, a chelator combines with and sequesters a therapeutic or diagnostic agent, such as a metal ion, which may be radioactive, and the combination is combined with a molecule that targets a cell, organ, etc., of interest. Examples of such molecules are antibodies of all types (e.g., polyclonal, monoclonal, chimeric, humanized, human, oligomeric, and fragmented antibodies), peptides, or ligands for receptors. For some discussion of relevant molecules, see Heppeler, et al., Chem. Eur. J, 5(7):1974-1981 (1999); Fu, et al., Eur. J. Org. Chem., 3966-3973 (2002). When combined in this way, the agent, e.g., a radio-pharmaceutical, targets, e.g., malignant tissue, and the risk of unspecific radiation, etc., is minimized.
Ideal chelators have high thermodynamic stability paralleling their chelates, and should also be relatively inert in vivo, to reduce complications caused by loss of the chelate.
Exemplary of chelators now in use are “DTPA” (diethylenetri amninetetraacetic acid), (Brechbiel, et al., J. Chem. Soc. Perkin Trans., 1:1173-1178 (1992)); and DOTA (1,4,7,10-tetraazacyclododecane-N, N′, N″, N′41 -tetraacetic acid), and derivatives like “BAD”, described by Kukis, et al., Canc. Res., 55:878-884 (1995). There is always interest, however, in new chelators with improved properties, or different properties, useful in different applications.
The chelator “TAME,” or 1,1,1-Tris-(aminomethyl)ethane, described by Geue, et al., Aust. J. Chem., 36:927-935 (1983), and incorporated by reference, is known as a tridentate ligand, and as a starting material for more complex ligands, as shown by Geue, et al., supra. For example, Green, et al., J. Am. Chem. Soc., 106:3689-3691 (1984) describe salicylaldimines of TAME, as chelating agents for incorporation of gallium ions, such as Ga3+ ions. Ga3+, when used with the positron emitting isotope 68Ga, is useful in “positron emission tomagraphy” or “PET.” The skilled artisan is very much aware of the usefulness of this technique in medical diagnosis. The chelating agent H3[(5-MeOsal)3tame], a TAME derivative, is described by Green, et al., J. Nucl. Med., 26:170-180 (1985), as being useful in assessing myocardial blood flow.
The structures of the chelators described supra are presented, in FIG. 4, for ease of reference.
While Viguier, et al., Eur. J. Inorg. Chem., 2001:1789-1795, incorporated by reference, discloses monofunctional TAME-based polyaminocarboxylic acids, the art does not describe any bifunctional chelating agents, based on TAME, which would be useful for radioimmuno imaging, or therapy. Similarly, there are no reports on TAME based, polyamino polycarboxylic acids.
It is a purpose of this invention to describe the synthesis of new chelators, based upon the basic TAME structure. This chelators are tripodol, and are bifunctional or monofunctional. When complexed with metal ions, for example, radioisotopes, such as 67Ga3+ and/or 68Ga3+, they are useful in the diagnostic and therapeutic modalities discussed supra.
Various features of the invention are described in the description which follows.